Camila Gonzalo-Hansen, Barbara Steurer, Roel C Janssens, Di Zhou, Marjolein van Sluis, Hannes Lans, Jurgen A Marteijn
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引用次数: 0
摘要
DNA 损伤会严重阻碍 RNA 聚合酶 II(Pol II)的基因转录,造成细胞功能障碍。转录偶联核苷酸切除修复(TC-NER)可专门清除此类转录阻碍损伤。TC-NER 的启动依赖于 CSB、CSA 和 UVSSA 蛋白;任何一种蛋白的缺失都会导致 TC-NER 的完全缺失。令人震惊的是,UVSSA 缺乏会导致轻微皮肤症状的紫外线敏感综合征(UVSS),而 CSA 或 CSB 活性丧失则会导致严重的科克恩综合征(CS),其特征是神经变性和过早衰老。迄今为止,这些截然不同的表型的内在机制仍不清楚。活细胞成像方法显示,在 TC-NER 熟练掌握的细胞中,病变停滞的 Pol II 会被迅速清除,而在 CSA 和 CSB 基因敲除(KO)细胞中,伸长的 Pol II 仍与损伤绑定,很可能会阻碍其他 DNA 转录过程,并使损伤免受替代修复途径的影响。相反,在 UVSSA KO 细胞中,Pol II 通过 VCP 介导的蛋白酶体降解从损伤中清除,而这种降解完全依赖于 CRL4CSA 泛素连接酶的活性。Pol II 的降解可能为 GG-NER 等替代修复机制提供了清除损伤的途径。总之,我们的数据表明,不能从染色质中清除病变停滞的 Pol II,而不是 TC-NER 缺乏,是 CS 中观察到的严重表型的原因。
Differential processing of RNA polymerase II at DNA damage correlates with transcription-coupled repair syndrome severity.
DNA damage severely impedes gene transcription by RNA polymerase II (Pol II), causing cellular dysfunction. Transcription-Coupled Nucleotide Excision Repair (TC-NER) specifically removes such transcription-blocking damage. TC-NER initiation relies on the CSB, CSA and UVSSA proteins; loss of any results in complete TC-NER deficiency. Strikingly, UVSSA deficiency results in UV-Sensitive Syndrome (UVSS), with mild cutaneous symptoms, while loss of CSA or CSB activity results in the severe Cockayne Syndrome (CS), characterized by neurodegeneration and premature aging. Thus far the underlying mechanism for these contrasting phenotypes remains unclear. Live-cell imaging approaches reveal that in TC-NER proficient cells, lesion-stalled Pol II is swiftly resolved, while in CSA and CSB knockout (KO) cells, elongating Pol II remains damage-bound, likely obstructing other DNA transacting processes and shielding the damage from alternative repair pathways. In contrast, in UVSSA KO cells, Pol II is cleared from the damage via VCP-mediated proteasomal degradation which is fully dependent on the CRL4CSA ubiquitin ligase activity. This Pol II degradation might provide access for alternative repair mechanisms, such as GG-NER, to remove the damage. Collectively, our data indicate that the inability to clear lesion-stalled Pol II from the chromatin, rather than TC-NER deficiency, causes the severe phenotypes observed in CS.
期刊介绍:
Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.